Five-step scale from benign to pathogenic. This variant is likely benign. Select a step to read what it means.
This variantScenario
BenignPathogenic
Likely benign.A likely benign classification under the recorded framework.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
About ATM
ATM encodes a kinase that acts as a master controller of the cellular DNA damage response: it detects double-strand breaks and coordinates DNA repair, cell cycle arrest, or apoptosis through downstream targets including p53, BRCA1, and CHK2. Loss-of-function mutations in both copies of ATM cause ataxia telangiectasia, an autosomal recessive disorder characterized by neurological problems, immune deficiency, and cancer predisposition. ATM functions as a tumor suppressor: individuals with ataxia telangiectasia are prone to childhood lymphomas, leukemias, and breast cancer, while carriers of a single altered copy have increased risk of breast, pancreatic, prostate, and other cancers. Somatic ATM mutations also occur in lymphoid malignancies and solid tumors, and ATM-deficient cancers are often especially sensitive to DNA-damaging treatments.
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Criteria may be applied incorrectly, sources may be misread, and a
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01The reasoning
How it was classified
The recorded framework is ClinGen ATM VCEP v1.5. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 2
BS3Supporting
BS3 · supporting
Met, Supporting: direct prime-editing screen classified c.2552A>G as Functional with High confidence and Combined_score 0.586774271783898, pending assay-approval review.
BP4Supporting
BP4 · supporting
Met, supporting: REVEL 0.099 is below the ATM VCEP BP4 missense threshold of <=0.249.
Recorded classification: Likely benign
Likely Benign: BS3 (supporting) plus BP4 (supporting) satisfy the ATM VCEP Version 1.5 Rule19 benign combination.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
24 / 1,613,990 alleles
gnomAD v4.1: 24 / 1,613,990 alleles. Recorded AF 1.487e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 7.95513e-06; MAF= 0.00080%, 2/251410 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000163026; MAF= 0.01630%, 1/6134 alleles, homozygotes = 0).
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. ATM, a kinase involved in the DNA damage response, is mutated in various solid and hematologic malignancies.
ACMG/AMP criteria under ClinGen ATM VCEP v1.5, with the data and sources behind each one.
28 criteria with recorded statuses: 2 met · 8 not met · 5 not assessed · 13 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
All three requested criteria are not applicable: the ATM VCEP restricts PVS1 to specified null mechanisms, PM4 to stop-loss variants, and explicitly marks BP3 not applicable; this variant is a missense substitution.
For this missense variant, the governing ATM VCEP framework supports no PS1, PM1, PM5, PP2, or BP1 evidence: PS1 lacks an established same-amino-acid pathogenic comparator, PM1 lacks an approved critical-domain or hotspot basis, PM5 is restricted to qualifying truncating/splice variants, and PP2/BP1 are explicitly not applicable.
For ATM version 1.5, PS2, PM6, and BS4 are not applicable; PP1 is applicable only to autosomal recessive ataxia-telangiectasia but cannot be assessed without documented affected relatives and informative segregation data.
The only variant-specific functional result found was the Sun et al. 2025 Table S1 direct screen result: Functional, High confidence, DeepATM_predicted=No, Combined_score=0.586774271783898.
No entry for c.2552A>G, p.Asp851Gly, or p.D851G was found in the ATM VCEP approved-assay calibration table; the resulting BS3 Supporting assignment is flagged for human review because the assay is not among the VCEP-listed approved assays.
No abnormal functional result supports PS3.
The governing framework is the ClinGen HBOP ATM VCEP v1.5 specification because an applicable gene-specific framework is present.
Only PS4, PP4, PP5, BP5, and BP6 were adjudicated.
No PP5 or BP6 criterion was triggered because the exact-variant ClinVar record has zero expert-panel submissions; ordinary laboratory submissions and aggregate labels were excluded.
The variant is an exonic missense substitution, so PP3 and BP4 are evaluated through the ATM VCEP missense computational path, while BP7 is not applicable.
PP3 is not met because REVEL 0.099 is below >0.7333 and SpliceAI maximum delta 0.074 is below >=0.2.
BP4 is met at supporting strength because REVEL 0.099 is <=0.249.
Population evidence was assessed under the ClinGen HBOP ATM VCEP v1.5 framework using the specified gnomAD v4 all-comers data.
The observed gnomAD v4.1 frequency is below the benign thresholds for BA1 and BS1 but is slightly above the VCEP PM2 cutoff; BS2 is explicitly not applicable under the VCEP.
No criteria match.
Met · 2
BS3SupportingMet, Supporting: direct prime-editing screen classified c.2552A>G as Functional with High confidence and Combined_score 0.586774271783898, pending assay-approval review.
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Reasoning
The Sun et al. 2025 ATM saturation prime-editing screen directly measured this variant (DeepATM_predicted=No), reported Classification=Functional with Confidence=High, and gave Combined_score=0.586774271783898. This supports retained function and therefore BS3 Supporting under the ATM VCEP rule for rescue of either an ATM-specific feature or radiosensitivity. However, the result is from a post-VCEP/non-listed assay rather than one of the three currently approved ATM assays, so the strength requires human review and is not upgraded.
Rule
ClinGen HBOP ATM VCEP v1.5 BS3: Supporting when a variant rescues either an ATM-specific feature or radiosensitivity; Moderate when it rescues both. The VCEP-approved assay table limits calibrated application to specified assays.
Evidence considered
The Sun et al. Table S1 row for c.2552A>G / D851G reports Combined_score=0.586774271783898, Classification=Functional, Confidence=High, and DeepATM_predicted=No, indicating direct prime-editing screen measurement rather than model extrapolation.
The ATM VCEP BS3 rule assigns Supporting when a variant rescues either an ATM-specific feature or radiosensitivity; Moderate requires rescue of both.
The ATM assay calibration table lists only Mitui 2009, Barone 2009, and Scott 2002 as approved assays, and the searched table contains no entry for c.2552A>G, p.Asp851Gly, or p.D851G.
Still missing
The file clingen_hbop_atm_supplementary_tables_1_and_2_v1.xlsx was searched for c.2552A>G, p.Asp851Gly, and p.D851G; no variant-specific entry was found.
The Sun et al. assay is not one of the three ATM VCEP-approved assays, so a human reviewer must confirm whether this direct measurement can receive BS3 under the current VCEP specification.
No variant-specific result from the approved Mitui 2009, Barone 2009, or Scott 2002 assays was available.
BP4SupportingMet, supporting: REVEL 0.099 is below the ATM VCEP BP4 missense threshold of <=0.249.
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Reasoning
The variant is missense, so the ATM VCEP missense BP4 path applies. The governing ATM VCEP v1.5 specifies BP4 supporting for missense variants with REVEL <=0.249. The observed REVEL score is 0.099, which meets that threshold. The laboratory policy in the governing materials directs BP4 for missense variants to use the missense REVEL path only and not to use a clean SpliceAI result as an independent benign assertion; applying that policy does not change the result because REVEL itself meets the VCEP missense threshold. The exact on-record Sun et al. 2025 Table S1 row also reports REVEL 0.099, but its functional classification is treated only as corroboration and is not required for BP4. Therefore BP4 is met at supporting strength.
The ClinGen HBOP ATM VCEP v1.5 rule specifies BP4 supporting for missense variants with REVEL <=0.249.
The case evidence reports a REVEL score of 0.099.
The governing laboratory policy restricts BP4 for missense variants to the REVEL missense path rather than independently using SpliceAI; this does not alter the outcome because REVEL 0.099 meets the missense threshold.
The exact row in Suppl_TableS1_PMID 40580951.xlsx is c.2552A>G / D851G, Missense, REVEL 0.099, Classification Functional, Confidence High, DeepATM_predicted No.
PS1Not met: no established pathogenic or likely pathogenic comparator for p.Asp851Gly was identified in the governing ATM PS1 evidence.
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Reasoning
The ATM VCEP PS1 specification permits PS1 for a missense variant only when it produces the same amino-acid change as a previously established pathogenic or likely pathogenic variant and splicing is ruled out for both alterations. The case variant is NM_000051.4:c.2552A>G, p.(Asp851Gly)/p.(D851G); the governing ATM_PS1_1.5.pdf.txt was searched for c.2552A>G, p.Asp851Gly, and p.D851G, with no entry found. The reviewed evidence does not identify an established pathogenic or likely pathogenic comparator producing the same p.Asp851Gly substitution, so the VCEP PS1 requirement is not met. SpliceAI max delta is 0.074, below the ATM PP3 splice threshold of 0.2, but this does not establish the required pathogenic same-amino-acid comparator.
Rule
ATM VCEP PS1: use for missense changes only when the same amino-acid change is established as pathogenic or likely pathogenic and splicing is ruled out for both alterations.
Evidence considered
The ATM VCEP framework states that missense PS1 requires the same amino-acid change as a previously established pathogenic variant, with splicing ruled out for both alterations.
The governing ATM PS1 full text was searched under c.2552A>G, p.Asp851Gly, and p.D851G; no variant-specific entry was found.
SpliceAI maximum delta was 0.074, below the ATM VCEP splice-prediction threshold of 0.2, but no pathogenic or likely pathogenic same-amino-acid comparator was established.
Still missing
No entry for c.2552A>G, p.Asp851Gly, or p.D851G was found in ATM_PS1_1.5.pdf.txt.
A curated pathogenic or likely pathogenic variant producing the same p.Asp851Gly amino-acid change was not identified in the reviewed evidence.
PM1Not met: ATM has no authoritative domain-table entry, and residue 851 has no documented significant hotspot evidence supporting PM1.
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Reasoning
The ATM VCEP framework marks PM1 as not applicable, and vcep_materials.json contains no domain_tables entry for ATM. Therefore there is no authoritative approved critical-domain list placing residue 851 in a PM1-eligible domain. The case evidence also reports that p.Asp851Gly does not lie in a statistically significant cancer hotspot. No validated ATM critical-domain or hotspot evidence supports PM1 for residue 851.
Rule
PM1 requires a validated critical functional domain or hotspot; the ATM VCEP framework marks PM1 not applicable and provides no authoritative ATM domain-table entry in this case.
Evidence considered
The ATM VCEP framework lists PM1 as Not Applicable.
vcep_materials.json contains domain_tables: {}, so no authoritative ATM functional-domain entry places residue 851 within a PM1-approved domain.
The case evidence reports no statistically significant hotspot for ATM D851.
Still missing
vcep_materials.json has an empty domain_tables object for ATM, so no authoritative complete ATM critical-domain list was available for residue-by-residue comparison.
No variant-specific significant hotspot record was available in the reviewed case evidence.
PM2Not met: gnomAD v4.1 combined AF is 0.00149%, above the ATM VCEP PM2 cutoff of at or below 0.001%.
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Reasoning
The ATM VCEP v1.5 specifies PM2 Supporting for frequency at or below 0.001% in gnomAD v4. The gnomAD v4.1 combined allele frequency is 1.486998e-05 (0.00149%), and the grpmax FAF is 1.03e-05 (0.00103%); both exceed the VCEP cutoff, so PM2 is not met. The VCEP does not direct use of the non-cancer subsets for this criterion, so the default all-comers gnomAD v4 dataset applies.
Rule
Frequency <=0.001% in gnomAD v4 dataset; if n=1 in a single subpopulation, that is sufficiently rare and PM2 Supporting would apply
Evidence considered
ATM VCEP v1.5 specifies PM2 Supporting for frequency at or below 0.001% in gnomAD v4.
gnomAD v4.1 reports combined AF 1.486998e-05, equivalent to 0.00149%, from 24/1,613,990 alleles, with zero homozygotes.
The ATM VCEP rule names gnomAD v4 without a non-cancer or exome-only restriction; therefore the all-comers gnomAD v4 totals are the governing source for this assessment.
PP3Not met: REVEL 0.099 and SpliceAI maximum delta 0.074 are below the ATM VCEP PP3 thresholds of >0.7333 and >=0.2.
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Reasoning
The variant is missense, so the ATM VCEP missense and splice-impact PP3 paths are in scope. The governing ATM VCEP v1.5 specifies PP3 for missense variants only when REVEL is >0.7333 or when SpliceAI predicts splicing impact with a score >=0.2. The observed REVEL score is 0.099 and the SpliceAI maximum delta score is 0.074, both below the applicable pathogenic thresholds. The on-record Sun et al. 2025 Table S1 contains an exact c.2552A>G / D851G row with REVEL 0.099, Classification Functional, Confidence High, and DeepATM_predicted No, but it does not pre-assign PP3; its functional-screen classification is not used as a computational PP3 code. Therefore PP3 is not met.
The ClinGen HBOP ATM VCEP v1.5 rule specifies PP3 supporting for missense variants with REVEL >0.7333 and for splicing impact with SpliceAI >=0.2.
The case evidence reports REVEL 0.099 and SpliceAI scores DS_AG 0.002, DS_AL 0.002, DS_DG 0.074, and DS_DL 0.003; the maximum delta is 0.074.
The exact row in Suppl_TableS1_PMID 40580951.xlsx is c.2552A>G / D851G, Missense, REVEL 0.099, Classification Functional, Confidence High, DeepATM_predicted No; no pre-assigned PP3 code is present in that row.
PP5Not met: ClinVar reports zero expert-panel submissions for this exact variant, so ordinary laboratory and aggregate classifications cannot support PP5.
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Reasoning
PP5 requires an exact-variant ClinVar expert-panel classification of Pathogenic or Likely pathogenic. ClinVar variation 233529 for NM_000051.4:c.2552A>G has no expert-panel submissions; the record is criteria provided, single submitter, with Uncertain significance from seven laboratories and Likely benign from one laboratory. Ordinary laboratory submissions and aggregate labels do not qualify, so PP5 is not met. The ATM VCEP also marks PP5 not applicable.
Rule
Apply only for an exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification; otherwise do not apply.
Evidence considered
ClinVar variation 233529 is the exact NM_000051.4:c.2552A>G record and reports expert_panel_submissions: 0.
The ClinVar record is criteria provided, single submitter, with seven Uncertain significance laboratory submissions and one Likely benign laboratory submission; none is an expert-panel classification.
The ATM HBOP VCEP v1.5 marks PP5 not applicable and states that the criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
BA1Not met: gnomAD v4.1 grpmax FAF is 0.00103%, below the ATM VCEP BA1 threshold of greater than 0.5%.
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Reasoning
The ATM VCEP v1.5 specifies BA1 when gnomAD v4 grpmax filtering allele frequency is greater than 0.5%. The gnomAD v4.1 grpmax FAF is 1.03e-05 (0.00103%), far below 0.5%, so BA1 is not met. The variant is observed in 24/1,613,990 combined alleles with no homozygotes; these observations do not approach the VCEP stand-alone benign threshold.
Rule
Grpmax Filtering AF >0.5% in gnomAD v4 dataset
Evidence considered
ATM VCEP v1.5 specifies BA1 for gnomAD v4 grpmax filtering AF greater than 0.5%.
gnomAD v4.1 reports grpmax FAF 1.03e-05, equivalent to 0.00103%, with 24/1,613,990 total alleles and zero homozygotes.
BS1Not met: gnomAD v4.1 grpmax FAF is 0.00103%, below the ATM VCEP BS1 threshold of greater than 0.05%.
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Reasoning
The ATM VCEP v1.5 specifies BS1 when gnomAD v4 grpmax filtering allele frequency is greater than 0.05%. The gnomAD v4.1 grpmax FAF is 1.03e-05 (0.00103%), below 0.05%, so BS1 is not met.
Rule
Grpmax Filtering AF >0.05% in gnomAD v4 dataset
Evidence considered
ATM VCEP v1.5 specifies BS1 for gnomAD v4 grpmax filtering AF greater than 0.05%.
gnomAD v4.1 reports grpmax FAF 1.03e-05, equivalent to 0.00103%.
BP6Not met: the exact variant has no ClinVar expert-panel Benign or Likely benign classification, only a single-laboratory Likely benign submission.
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Reasoning
BP6 requires an exact-variant ClinVar expert-panel classification of Benign or Likely benign. ClinVar variation 233529 for NM_000051.4:c.2552A>G has zero expert-panel submissions; its Likely benign classification is from one clinical laboratory and the aggregate record is Uncertain significance. These non-expert and aggregate labels cannot trigger BP6. The ATM VCEP also marks BP6 not applicable.
Rule
Apply only for an exact-variant ClinVar expert-panel Benign or Likely benign classification; otherwise do not apply.
Evidence considered
ClinVar variation 233529 is the exact NM_000051.4:c.2552A>G record and reports expert_panel_submissions: 0.
The record contains one Likely benign clinical-laboratory submission, seven Uncertain significance clinical-laboratory submissions, and an aggregate Uncertain significance label; none is an expert-panel classification.
The ATM HBOP VCEP v1.5 marks BP6 not applicable and states that the criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
PS3Not assessed: the direct screen classified c.2552A>G as Functional, High confidence, not as an abnormal ATM-specific readout supporting PS3.
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Reasoning
No variant-specific abnormal functional result was identified. The ATM VCEP-approved assay calibration requires variant testing in the Mitui 2009 (PMID:18634022), Barone 2009 (PMID:19431188), or Scott 2002 (PMID:11805335) assays, with PS3 Supporting for failure of an ATM-specific feature and PS3 Moderate only when failure of both an ATM-specific feature and radiosensitivity is demonstrated. The searched calibration file contains no c.2552A>G, p.Asp851Gly, or p.D851G entry, and the Sun et al. Table S1 entry classifies the variant as Functional, High confidence, DeepATM_predicted=No rather than as non-functional. Therefore no PS3 strength is assigned.
Rule
ClinGen HBOP ATM VCEP v1.5 PS3: do not use as strong; Supporting requires failure to rescue an ATM-specific feature, and Moderate requires failure to rescue both an ATM-specific feature and radiosensitivity.
Evidence considered
The ATM VCEP specification states that PS3 Supporting is used when a variant fails to rescue an ATM-specific feature, while PS3 Moderate requires failure of both an ATM-specific feature and radiosensitivity; radiosensitivity alone receives no weight.
The Sun et al. Table S1 row for c.2552A>G / D851G reports Classification=Functional, Confidence=High, and DeepATM_predicted=No, which is direct screen evidence but not evidence of abnormal function.
The ATM approved-assay calibration table was searched under c.2552A>G, p.Asp851Gly, and p.D851G; no variant-specific result was present.
Still missing
The file clingen_hbop_atm_supplementary_tables_1_and_2_v1.xlsx was searched for c.2552A>G, p.Asp851Gly, and p.D851G; no variant-specific entry was found.
No variant-specific abnormal kinase-activity or qualifying combined kinase-activity/radiosensitivity result from the VCEP-approved Mitui 2009, Barone 2009, or Scott 2002 assays was available.
PS4Not assessed: no variant-specific case-control p-value, effect estimate, or confidence interval is available to compare with the VCEP PS4 thresholds.
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Reasoning
The ATM HBOP VCEP v1.5 permits PS4 Strong for case-control studies only when p-value <=.05 and (odds ratio, hazard ratio, or relative risk >=2 OR lower 95% CI >=1.5). No variant-specific case-control counts, p-value, effect estimate, or confidence interval for NM_000051.4:c.2552A>G were identified. The available literature extracts do not report this exact variant, so enrichment cannot be adjudicated. The governing operator is quoted literally: p-value <=.05 AND (Odds ratio, hazard ratio, or relative risk >=2 OR lower 95% CI >=1.5); no numeric substitution is possible because the required case-control metrics are unavailable.
Rule
Case-control studies; p-value <=.05 AND (Odds ratio, hazard ratio, or relative risk >=2 OR lower 95% CI >=1.5).
Evidence considered
The ATM HBOP VCEP v1.5 PS4 rule states: Case-control studies; p-value <=.05 AND (Odds ratio, hazard ratio, or relative risk >=2 OR lower 95% CI >=1.5).
The exact ATM c.2552A>G / p.(D851G) variant was not reported in the evaluated paper extracts, and no case-control metric for this exact variant was available.
Still missing
Variant-specific case and control counts are unavailable.
A variant-specific p-value, odds ratio/hazard ratio/relative risk, and lower 95% confidence interval are unavailable.
PM3Not assessed: no affected A-T proband, phase, trans partner, or homozygous observation was available to assign PM3 points under the ATM VCEP table.
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Reasoning
The governing ClinGen HBOP ATM VCEP v1.5 PM3/BP2 specification requires scored observations in unrelated A-T probands, classified by phenotype and phase: confident phenotype observations contribute 4.0 points when confirmed in trans, 2.0 when phase is unknown, 1.0 when the second variant is unidentified or a VUS, and 2.0 for homozygous observations (maximum two); consistent phenotype observations contribute half these values. The case evidence contains no affected-proband observation, A-T phenotype description, second ATM variant, phase determination, trans/cis evidence, or homozygous affected individual for ATM c.2552A>G (p.Asp851Gly). The governing file ATM_PM3_BP2_1.5.pdf was searched for c.2552A>G, p.Asp851Gly, and p.D851G and contains no variant-specific entry. Therefore no PM3 points or strength can be assigned. The variant is rare in gnomAD v4 (grpmax FAF 1.03e-05), satisfying the VCEP rarity prerequisite, but population rarity is not PM3 evidence.
Rule
ATM VCEP v1.5 PM3/BP2 table: PM3 Supporting=1.0 point, Moderate=2.0 points, Strong=4.0 points, Very Strong=8.0 points; affected-proband points depend on phenotype and phase.
Evidence considered
ClinGen HBOP ATM VCEP v1.5 specifies PM3 scoring for unrelated A-T probands as 4.0/2.0/1.0/2.0 points for a confident phenotype depending on confirmed trans, phase unknown, second variant unidentified or VUS, or homozygosity, respectively; consistent phenotypes receive half those values, and PM3 strength is Supporting at 1.0, Moderate at 2.0, Strong at 4.0, and Very Strong at 8.0 points.
The case evidence provides no affected A-T proband, A-T phenotype, second ATM variant, phase, trans/cis relationship, or affected homozygous observation for ATM c.2552A>G (p.Asp851Gly).
ATM_PM3_BP2_1.5.pdf was searched for c.2552A>G, p.Asp851Gly, and p.D851G; no variant-specific entry was found.
gnomAD v4 reports grpmax FAF 1.03e-05 for the variant, below the VCEP's 0.01% rarity prerequisite; this establishes rarity only and does not provide PM3 points.
Still missing
No variant-specific entry for c.2552A>G, p.Asp851Gly, or p.D851G was found in ATM_PM3_BP2_1.5.pdf.
No unrelated A-T affected-proband observation with phenotype classification was available.
No confirmed-in-trans or phase-unknown pathogenic/likely pathogenic ATM partner was available.
No eligible homozygous affected individual or second-variant-unidentified/VUS observation was available.
PP1Not assessed: zero affected relatives or informative segregation meioses are documented, so the VCEP's 1/2/3-relative PP1 thresholds cannot be applied.
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Reasoning
The ClinGen HBOP ATM VCEP version 1.5 permits PP1 only for the autosomal recessive ataxia-telangiectasia condition, where affected relatives must have both variants identified in the proband; strength is supporting for one affected relative, moderate for two, and strong for at least three. The case evidence provides no documented affected relatives, parental phase, meioses, or variant-specific family segregation data, so no PP1 strength can be assigned.
Rule
AR Condition: Affected relatives must have both variants identified in proband. Supporting: segregation in 1 affected relative; Moderate: segregation in 2 affected relatives; Strong: segregation in >=3 affected relatives.
Evidence considered
ClinGen HBOP ATM VCEP version 1.5 restricts PP1 to the autosomal recessive condition and requires affected relatives to have both variants identified in the proband.
The VCEP assigns PP1 supporting strength for segregation in one affected relative, moderate for two, and strong for at least three affected relatives.
No variant-specific affected-relative, parental-phase, meiosis, or segregation observation is present in the available case evidence.
Still missing
Affected relatives with both ATM variants identified in the proband are not documented.
Informative parental phase and segregation results are not documented.
The number of informative meioses is not documented.
BP2Not assessed: no unaffected adult with a pathogenic ATM variant in trans or eligible homozygous observation was available for BP2 scoring.
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Reasoning
The governing ClinGen HBOP ATM VCEP v1.5 PM3/BP2 specification requires observations in unaffected non-A-T adults older than 18 years who carry ATM c.2552A>G (p.Asp851Gly) with a pathogenic or likely pathogenic ATM variant in trans, or eligible homozygous observations, and excludes gnomAD frequency-based observations from BP2. The case evidence contains no unaffected adult with this variant, no non-A-T phenotype assessment, no pathogenic/likely pathogenic ATM partner, no phase determination, and no eligible homozygous unaffected observation. The governing file ATM_PM3_BP2_1.5.pdf was searched for c.2552A>G, p.Asp851Gly, and p.D851G and contains no variant-specific entry. Consequently, no BP2 points can be assigned: the available evidence does not establish -1 point for Supporting, -2 points for Moderate, or <=-4 points for Strong BP2.
Rule
ATM VCEP v1.5 PM3/BP2 table: BP2 Supporting=-1.0 point, Moderate=-2.0 points, Strong<=-4.0 points; use unaffected non-A-T adults or eligible homozygous clinical/research-cohort observations only.
Evidence considered
ClinGen HBOP ATM VCEP v1.5 specifies BP2 scoring for an unaffected non-A-T adult carrying the variant with a pathogenic or likely pathogenic ATM variant as -4.0 points when confirmed in trans, -2.0 when phase is unknown, and for eligible homozygous observations -2.0 in a laboratory setting or -1.0 in a database setting; BP2 strength is Supporting at -1.0, Moderate at -2.0, and Strong at <=-4.0 points.
The case evidence provides no unaffected adult, non-A-T status, pathogenic/likely pathogenic ATM partner, phase, or eligible homozygous cohort observation for ATM c.2552A>G (p.Asp851Gly).
ATM_PM3_BP2_1.5.pdf was searched for c.2552A>G, p.Asp851Gly, and p.D851G; no variant-specific entry was found.
The ATM VCEP specification states that homozygous observations used for BP2 must be phenotyped clinical or research-cohort individuals and must not be frequency-based gnomAD observations; gnomAD v4 reports zero homozygotes but does not supply BP2 evidence.
Still missing
No variant-specific entry for c.2552A>G, p.Asp851Gly, or p.D851G was found in ATM_PM3_BP2_1.5.pdf.
No unaffected non-A-T adult observation was available.
No pathogenic/likely pathogenic ATM co-occurring variant classified under the VCEP was available.
No confirmed or phase-unknown trans relationship was available.
No eligible homozygous unaffected observation from a clinical or research cohort was available; gnomAD observations cannot substitute for this BP2 evidence.
Not applicable · 13· recorded as not applicableShow reasons ▾Hide reasons ▴PVS1N/ANot applicable: c.2552A>G is a missense substitution producing p.Asp851Gly, outside the ATM VCEP's PVS1 null-variant mechanisms.
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Reasoning
PVS1 is not applicable because NM_000051.4:c.2552A>G produces NP_000042.3:p.(Asp851Gly), p.(D851G), a missense substitution rather than a nonsense, frameshift, canonical splice-site, initiation-codon, or exon-deletion null variant. The governing ClinGen HBOP ATM VCEP v1.5 PVS1 guide limits this criterion to those null-variant mechanisms; therefore no NMD-triggering premature termination, exon-loss consequence, or protein-length reduction is present for this variant, and no PVS1 strength tier can be assigned.
Rule
ClinGen HBOP ATM VCEP v1.5 PVS1 guide: PVS1 applies to specified null-variant mechanisms; this missense substitution is outside the rule scope.
Evidence considered
Variant normalization identifies NM_000051.4:c.2552A>G as NP_000042.3:p.(Asp851Gly), p.(D851G), with missense consequence.
The ClinGen HBOP ATM VCEP v1.5 PVS1 specification defines the applicable null-variant classes as nonsense, frameshift, canonical +/-1 or 2 splice-site, initiation-codon, and single- or multi-exon deletion variants.
The variant assessment identifies the consequence as missense and does not identify a premature termination, NMD event, exon loss, or protein-length change.
Still missing
No c.2552A>G, p.Asp851Gly, or p.D851G entry was found in ATM_PVS1_1.5.pdf.txt; this file governs null-variant PVS1 decisions rather than missense substitutions.
PS2VCEPNot applicable: ATM VCEP v1.5 excludes PS2 because informative de novo observations are not established for ATM-related conditions.
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Reasoning
The ClinGen HBOP ATM VCEP version 1.5 specifies PS2 as not applicable for both autosomal dominant ATM-related cancer predisposition and autosomal recessive ataxia-telangiectasia, because informative de novo observations have not been established and de novo evidence is not informative for the recessive condition. No case-specific parental testing or de novo observation is available to override that specification.
VCEP rule
Do not use for AD or AR disease: Informative de novo occurrences have not yet been observed and de novo AR conditions are unlikely to be informed by phase.
Evidence considered
ClinGen HBOP ATM VCEP version 1.5 labels PS2 not applicable and instructs reviewers not to use it for autosomal dominant or autosomal recessive ATM disease.
The available case evidence contains no confirmed parental testing, maternity and paternity confirmation, or other informative de novo observation for NM_000051.4:c.2552A>G.
Still missing
No case-specific parental testing or confirmed de novo observation is documented.
PM4N/ANot applicable: p.Asp851Gly is a missense substitution, whereas ATM VCEP PM4 is specified only for stop-loss variants.
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Reasoning
PM4 is not applicable. The ATM VCEP v1.5 specification limits PM4 to stop-loss variants, while NM_000051.4:c.2552A>G is a missense substitution producing p.Asp851Gly. It neither removes the normal stop codon nor creates an in-frame protein-length change.
Rule
ClinGen HBOP ATM VCEP v1.5 PM4: use for stop-loss variants; this missense substitution is not applicable.
Evidence considered
The ATM VCEP v1.5 PM4 rule states: use for stop-loss variants.
NM_000051.4:c.2552A>G is a missense substitution producing p.Asp851Gly, with no stop-loss or protein-length alteration.
PM5N/ANot applicable: p.Asp851Gly is missense, whereas the ATM PM5 rule applies to qualifying truncating or splice variants.
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Reasoning
The governing ATM VCEP PM5 rule is restricted to frameshifting or truncating variants with premature termination codons upstream of p.Arg3047, and to splice variants meeting the specified premature-termination/NMD conditions. NM_000051.4:c.2552A>G produces the missense substitution p.Asp851Gly, so this missense variant is outside the VCEP PM5 rule.
Rule
ATM VCEP PM5: apply only to qualifying frameshifting/truncating variants or specified splice variants; not applicable to this missense variant.
Evidence considered
The ATM VCEP PM5 specification applies to frameshifting/truncating variants with premature termination codons upstream of p.Arg3047 and specified splice variants, not missense substitutions.
The variant assessment identifies NM_000051.4:c.2552A>G as a missense variant producing p.Asp851Gly.
PM6VCEPNot applicable: ATM VCEP v1.5 excludes PM6 because assumed de novo status is not informative for ATM disease.
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Reasoning
The ClinGen HBOP ATM VCEP version 1.5 specifies PM6 as not applicable for autosomal dominant ATM-related cancer predisposition and autosomal recessive ataxia-telangiectasia. The specification states that informative de novo occurrences have not been observed and that assumed de novo status is not informative for the recessive condition; no case-specific assumed de novo observation is documented.
VCEP rule
Do not use for AD or AR disease: Informative de novo occurrences have not yet been observed and de novo AR conditions are unlikely to be informed by phase.
Evidence considered
ClinGen HBOP ATM VCEP version 1.5 labels PM6 not applicable and instructs reviewers not to use it for autosomal dominant or autosomal recessive ATM disease.
The available case evidence contains no documented parental testing or assumed de novo finding for NM_000051.4:c.2552A>G.
Still missing
No case-specific parental testing or assumed de novo observation is documented.
PP2VCEPNot applicable: the ATM VCEP explicitly designates PP2 as Not Applicable.
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Reasoning
The ATM VCEP framework explicitly marks PP2 as Not Applicable. Accordingly, no generic PP2 inference based on the proportion of pathogenic missense variants in ATM was applied.
VCEP rule
ATM VCEP PP2 applicability: Not Applicable.
Evidence considered
The ATM Version 1.5 VCEP framework explicitly lists PP2 as Not Applicable.
PP4VCEPNot applicable: the ATM VCEP disallows separate PP4 use because the relevant phenotypes are nonspecific or incorporated into PM3/BP2.
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Reasoning
The ATM HBOP VCEP v1.5 marks PP4 not applicable. For autosomal dominant ATM-related cancer predisposition, breast cancer has genetic heterogeneity and no phenotype readily distinguishes hereditary from sporadic disease; for autosomal recessive ataxia-telangiectasia, phenotype evidence is incorporated into the PM3/BP2 framework rather than used as a separate PP4 line.
VCEP rule
Not applicable under ATM HBOP VCEP v1.5.
Evidence considered
The ATM HBOP VCEP v1.5 PP4 instruction states not to use PP4 for autosomal dominant ATM-related cancer because of genetic heterogeneity and nonspecific phenotypes, and not to use it separately for autosomal recessive disease because phenotype evidence is built into PM3/BP2.
BS2VCEPNot applicable: the ATM VCEP marks BS2 as not applicable, despite zero homozygotes in gnomAD v4.1.
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Reasoning
The governing ATM VCEP v1.5 marks BS2 as Not Applicable. Although gnomAD v4.1 reports zero homozygotes, this criterion is not used under the applicable gene-specific framework.
Evidence considered
ATM VCEP v1.5 lists BS2 as Not Applicable.
gnomAD v4.1 reports zero homozygotes for 24 observed alleles.
BS4VCEPNot applicable: ATM VCEP v1.5 assigns no BS4 weight because informative non-segregation is too rare and cancer phenocopies confound interpretation.
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Reasoning
The ClinGen HBOP ATM VCEP version 1.5 specifies BS4 as not applicable. It states that informative lack of co-segregation in ataxia-telangiectasia families is too rare to receive weight at this time, while cautioning that apparent non-segregation in low-penetrance autosomal dominant ATM-related cancer predisposition can be misleading.
VCEP rule
AD Condition: Co-segregation analysis in low penetrance genes can lead to false positive results. AR Condition: Informative instances of lack of co-segregation in A-T families are too rare to be considered for weight at this time.
Evidence considered
ClinGen HBOP ATM VCEP version 1.5 labels BS4 not applicable.
The VCEP states that informative lack of co-segregation in ataxia-telangiectasia families is too rare to receive weight and warns that low-penetrance cancer phenotypes can produce misleading non-segregation.
Still missing
No case-specific non-segregation analysis is documented.
BP1VCEPNot applicable: the ATM VCEP explicitly designates BP1 as Not Applicable.
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Reasoning
The ATM VCEP framework explicitly marks BP1 as Not Applicable. No generic BP1 inference for a missense variant in a gene where truncating variants are known to be non-pathogenic was applied.
VCEP rule
ATM VCEP BP1 applicability: Not Applicable.
Evidence considered
The ATM Version 1.5 VCEP framework explicitly lists BP1 as Not Applicable.
BP3VCEPNot applicable: the ATM VCEP marks BP3 not applicable, and p.Asp851Gly is not a repetitive-region in-frame insertion or deletion.
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Reasoning
BP3 is not applicable under the ATM VCEP v1.5 specification, which explicitly marks BP3 as not applicable. The variant is also a single-residue missense substitution rather than an in-frame insertion or deletion in a repetitive region without known function, so there is no repeat-region protein-length alteration to support BP3.
VCEP rule
ClinGen HBOP ATM VCEP v1.5 BP3 applicability: Not Applicable.
Evidence considered
The ATM VCEP v1.5 specification explicitly lists BP3 as Not Applicable.
NM_000051.4:c.2552A>G produces p.Asp851Gly, a missense substitution with no insertion, deletion, repeat-region alteration, or protein-length change.
BP5VCEPNot applicable: the ATM VCEP explicitly prohibits BP5 because alternate pathogenic variants can co-occur without a distinguishable phenotype.
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Reasoning
The ATM HBOP VCEP v1.5 marks BP5 not applicable and explicitly instructs not to use it because cases with multiple pathogenic variants may have no noticeable phenotype difference and ATM's low penetrance increases the chance of co-occurring pathogenic variants. No BP5 assignment is therefore permitted under the governing specification.
VCEP rule
Not applicable under ATM HBOP VCEP v1.5; do not use.
Evidence considered
The ATM HBOP VCEP v1.5 BP5 instruction states: Do not use, citing observed multiple pathogenic variants without a noticeable phenotype difference and ATM's low penetrance.
BP7N/ANot applicable: c.2552A>G produces the missense substitution p.Asp851Gly, not a synonymous variant.
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Reasoning
BP7 applies only to synonymous or qualifying deep-intronic variants. This variant is an exonic missense substitution, c.2552A>G (p.Asp851Gly/p.D851G), so BP7 is outside its criterion scope and is not evaluated.
Rule
ATM VCEP v1.5 BP7: synonymous and qualifying deep-intronic variants only.
Evidence considered
The case normalization identifies c.2552A>G as NP_000042.3:p.(Asp851Gly), and the exact VCEP Table S1 row labels the consequence as Missense.
The ATM VCEP v1.5 BP7 rule applies to synonymous and qualifying deep-intronic variants, not missense substitutions.
AF 1.5e-05 · 24 / 1,613,990 alleles · 0 hom · FAF 1e-05
Remaining individuals4 / 62,482
6.4e-05
European (non-Finnish)19 / 1,179,964
1.6e-05
African/African American1 / 74,936
1.3e-05
0 alternate alleles recorded in 7 other groups: Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish.
gnomAD v2.1
AF 8e-06 · 2 / 251,410 alleles · 0 hom
Remaining individuals1 / 6,134
0.00016
European (non-Finnish)1 / 113,724
8.8e-06
0 alternate alleles recorded in 6 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.487e-05; MAF= 0.00149%, 24/1613990 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 6.40184e-05; MAF= 0.00640%, 4/62482 alleles, homozygotes = 0); grpmax FAF= 1.03e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 7.95513e-06; MAF= 0.00080%, 2/251410 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000163026; MAF= 0.01630%, 1/6134 alleles, homozygotes = 0).
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
SpliceAI and Pangolin
SpliceAI acceptor lossat -85 bp
0.002
SpliceAI acceptor gainat -437 bp
0.002
SpliceAI donor lossat +86 bp
0.003
SpliceAI donor gainat -1 bp
0.074
Pangolin splice lossmagnitude shown
-0.017
Pangolin splice gain
0.050
Other predictors
REVEL
0.099
BayesDel
-0.532
How the predictions were used
BP4SupportingMet, supporting: REVEL 0.099 is below the ATM VCEP BP4 missense threshold of <=0.249.
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Reasoning
The variant is missense, so the ATM VCEP missense BP4 path applies. The governing ATM VCEP v1.5 specifies BP4 supporting for missense variants with REVEL <=0.249. The observed REVEL score is 0.099, which meets that threshold. The laboratory policy in the governing materials directs BP4 for missense variants to use the missense REVEL path only and not to use a clean SpliceAI result as an independent benign assertion; applying that policy does not change the result because REVEL itself meets the VCEP missense threshold. The exact on-record Sun et al. 2025 Table S1 row also reports REVEL 0.099, but its functional classification is treated only as corroboration and is not required for BP4. Therefore BP4 is met at supporting strength.
The ClinGen HBOP ATM VCEP v1.5 rule specifies BP4 supporting for missense variants with REVEL <=0.249.
The case evidence reports a REVEL score of 0.099.
The governing laboratory policy restricts BP4 for missense variants to the REVEL missense path rather than independently using SpliceAI; this does not alter the outcome because REVEL 0.099 meets the missense threshold.
The exact row in Suppl_TableS1_PMID 40580951.xlsx is c.2552A>G / D851G, Missense, REVEL 0.099, Classification Functional, Confidence High, DeepATM_predicted No.
PP3Not met: REVEL 0.099 and SpliceAI maximum delta 0.074 are below the ATM VCEP PP3 thresholds of >0.7333 and >=0.2.
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Reasoning
The variant is missense, so the ATM VCEP missense and splice-impact PP3 paths are in scope. The governing ATM VCEP v1.5 specifies PP3 for missense variants only when REVEL is >0.7333 or when SpliceAI predicts splicing impact with a score >=0.2. The observed REVEL score is 0.099 and the SpliceAI maximum delta score is 0.074, both below the applicable pathogenic thresholds. The on-record Sun et al. 2025 Table S1 contains an exact c.2552A>G / D851G row with REVEL 0.099, Classification Functional, Confidence High, and DeepATM_predicted No, but it does not pre-assign PP3; its functional-screen classification is not used as a computational PP3 code. Therefore PP3 is not met.
The ClinGen HBOP ATM VCEP v1.5 rule specifies PP3 supporting for missense variants with REVEL >0.7333 and for splicing impact with SpliceAI >=0.2.
The case evidence reports REVEL 0.099 and SpliceAI scores DS_AG 0.002, DS_AL 0.002, DS_DG 0.074, and DS_DL 0.003; the maximum delta is 0.074.
The exact row in Suppl_TableS1_PMID 40580951.xlsx is c.2552A>G / D851G, Missense, REVEL 0.099, Classification Functional, Confidence High, DeepATM_predicted No; no pre-assigned PP3 code is present in that row.
BP7N/ANot applicable: c.2552A>G produces the missense substitution p.Asp851Gly, not a synonymous variant.
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Reasoning
BP7 applies only to synonymous or qualifying deep-intronic variants. This variant is an exonic missense substitution, c.2552A>G (p.Asp851Gly/p.D851G), so BP7 is outside its criterion scope and is not evaluated.
Rule
ATM VCEP v1.5 BP7: synonymous and qualifying deep-intronic variants only.
Evidence considered
The case normalization identifies c.2552A>G as NP_000042.3:p.(Asp851Gly), and the exact VCEP Table S1 row labels the consequence as Missense.
The ATM VCEP v1.5 BP7 rule applies to synonymous and qualifying deep-intronic variants, not missense substitutions.
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
Germline Testing Data Validate Inferences of Mutational Status for Variants Detected From Tumor-Only Sequencing.
Jalloul N et al. · 2021
The study reports gene-level tumor-only sequencing findings involving ATM but does not explicitly mention c.2552A>G or p.(D851G), and therefore supplies no exact-variant PS4 evidence.
LOH was demonstrated for all PGV (13 of 13) in PALB2, TP53, ATM, CDH1, and CHEK2 in all tumor types.
Results, paragraph discussing hereditary breast cancer genes and LOH; Figure 5B
The emerging landscape of breast cancer susceptibility.
This review discusses ATM as a breast-cancer susceptibility gene and describes gene-level ATM biology and risk, but it does not report the exact c.2552A>G / p.(D851G) variant or a variant-specific case-control estimate.
Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women: U.S. Preventive Services Task Force recommendation statement.
This paper focuses on BRCA1 and BRCA2 risk assessment and does not mention ATM or the exact c.2552A>G / p.(D851G) variant, so it provides no PS4 evidence.
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.487e-05; MAF= 0.00149%, 24/1613990 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 6.40184e-05; MAF= 0.00640%, 4/62482 alleles, homozygotes = 0); grpmax FAF= 1.03e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 7.95513e-06; MAF= 0.00080%, 2/251410 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000163026; MAF= 0.01630%, 1/6134 alleles, homozygotes = 0).
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (7 clinical laboratories) and as Likely benign (1 clinical laboratory). (ClinVarID = 233529)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.07). REVEL score = 0.099. BayesDel score = -0.531721.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. ATM, a kinase involved in the DNA damage response, is mutated in various solid and hematologic malignancies.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
This variant was interpreted by pipeline 8.0.0.
The current version is 11.0.07.
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